Edalat, Lena and Stegen, Benjamin and Klumpp, Lukas and Haehl, Erik and Schilbach, Karin and Lukowski, Robert and Kuehnle, Matthias and Bernhardt, Guenther and Buschauer, Armin and Zips, Daniel and Ruth, Peter and Huber, Stephan M. (2016) BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells. ONCOTARGET, 7 (12). pp. 14259-14278. ISSN 1949-2553,
Full text not available from this repository. (Request a copy)Abstract
Infiltration of the brain by glioblastoma cells reportedly requires Ca2+ signals and BK K+ channels that program and drive glioblastoma cell migration, respectively. Ionizing radiation (IR) has been shown to induce expression of the chemokine SDF-1, to alter the Ca2+ signaling, and to stimulate cell migration of glioblastoma cells. Here, we quantified fractionated IR-induced migration/brain infiltration of human glioblastoma cells in vitro and in an orthotopic mouse model and analyzed the role of SDF-1/CXCR4 signaling and BK channels. To this end, the radiation-induced migratory phenotypes of human T98G and far-red fluorescent U-87MG-Katushka glioblastoma cells were characterized by mRNA and protein expression, fura-2 Ca2+ imaging, BK patch-clamp recording and transfilter migration assay. In addition, U-87MG-Katushka cells were grown to solid glioblastomas in the right hemispheres of immunocompromised mice, fractionated irradiated (6 MV photons) with 5 x 0 or 5 x 2 Gy, and SDF-1, CXCR4, and BK protein expression by the tumor as well as glioblastoma brain infiltration was analyzed in dependence on BK channel targeting by systemic paxilline application concomitant to IR. As a result, IR stimulated SDF-1 signaling and induced migration of glioblastoma cells in vitro and in vivo. Importantly, paxilline blocked IR-induced migration in vivo. Collectively, our data demonstrate that fractionated IR of glioblastoma stimulates and BK K+ channel targeting mitigates migration and brain infiltration of glioblastoma cells in vivo. This suggests that BK channel targeting might represent a novel approach to overcome radiation-induced spreading of malignant brain tumors during radiotherapy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | VASCULAR ENDOTHELIAL GROWTH; IRRADIATED LEUKEMIA-CELLS; ADJUVANT TEMOZOLOMIDE; PROGENITOR CELLS; RADIOTHERAPY; MECHANISM; INVASION; SURVIVAL; CXCR4; CONCOMITANT; glioma; radiation therapy; patch-clamp recording; fura-2 Ca2(+) imaging; transfilter migration |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Apr 2019 10:28 |
| Last Modified: | 03 Apr 2019 10:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3228 |
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